Process for the preparation of 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles from cyclohexanes and cyclohexanones as intermediates

ABSTRACT

The present invention relates to processes for the preparation of 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles (5a) from cyclohexanes (2a) and cyclohexanones (3a) as intermediate.

TECHNICAL FIELD

The present invention relates to processes for the preparation of2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles and to novelcyclohexanes and cyclohexanones for use in these processes.

BACKGROUND ART

Certain 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles are known tohave dopamine D-2 activity and are therefore potentially useful aspharmaceuticals for the treatment of psychiatric disorders such asschizophrenia and Alzheimer's disease. One such compound, thedihydrochloride salt of(S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole I(pramipexole), is marketed as a pharmaceutical for the treatment ofParkinson's disease. The numbering of pramipexole I is indicated below.

Processes for the preparation of2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles are disclosed inpatents U.S. Pat. No. 4,843,086, U.S. Pat. No. 4,886,812 and patentapplications WO 02/22590 A1 and WO 02/22591 A1. A procedure to thesetypes of compound is also disclosed by C. S. Schneider and J. Mierau inJ. Med. Chem., 1987, vol. 30, pages 494-498.

However, known processes for the preparation of2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles are not satisfactory,particularly for industrial scale manufacture, as they have been foundto be low yielding and involve the use of hazardous and difficult tohandle reagents such as bromine, hydrazine and potassium chromate.

SUMMARY OF THE INVENTION

A first aspect of the present invention is a process for the preparationof a 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole 5a

or a salt thereof, comprising the steps of:

(a) reductively aminating a protected cyclohexandione 1p with an amineR¹R²NH to yield a protected 4-amino-cyclohexanone 2p:

wherein P is a protected ketone functionality, and R¹ and R² are anyatom or group or, together with the nitrogen to which they are attached,form a ring;

(b) deprotecting the protected 4-amino-cyclohexanone 2p to yield anunprotected 4-amino-cyclohexanone 3a

(c) treating the unprotected 4-amino-cyclohexanone 3a with iodine and asubstituted thiourea H₂N(C═S)NHR³, wherein R³ is any atom or group, toyield the 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole 5a or a saltthereof.

For the purposes of the present invention, an “alkyl” group is definedas a monovalent saturated hydrocarbon, which may be straight-chained orbranched, or be or include cyclic groups. Examples of alkyl groups aremethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl andn-pentyl groups. Preferably an alkyl group is straight-chained orbranched and does not include any heteroatoms in its carbon skeleton.Preferably an alkyl group is a C₁-C₁₂ alkyl group, which is defined asan alkyl group containing from 1 to 12 carbon atoms. More preferably analkyl group is a C₁-C₆ alkyl group, which is defined as an alkyl groupcontaining from 1 to 6 carbon atoms. An “alkylene” group is similarlydefined as a divalent alkyl group.

An “alkenyl” group is defined as a monovalent hydrocarbon, whichcomprises at least one carbon-carbon double bond, which may bestraight-chained or branched, or be or include cyclic groups. Examplesof alkenyl groups are vinyl, allyl, but-1-enyl and but-2-enyl groups.Preferably an alkenyl group is straight-chained or branched and does notinclude any heteroatoms in its carbon skeleton. Preferably an alkenylgroup is a C₂-C₁₂ alkenyl group, which is defined as an alkenyl groupcontaining from 2 to 12 carbon atoms. More preferably an alkenyl groupis a C₂-C₆ alkenyl group, which is defined as an alkenyl groupcontaining from 2 to 6 carbon atoms. An “alkenylene” group is similarlydefined as a divalent alkenyl group.

An “alkynyl” group is defined as a monovalent hydrocarbon, whichcomprises at least one carbon-carbon triple bond, which may bestraight-chained or branched, or be or include cyclic groups. Examplesof alkynyl groups are ethynyl, propargyl, but-1-ynyl and but-2-ynylgroups. Preferably an alkynyl group is straight-chained or branched anddoes not include any heteroatoms in its carbon skeleton. Preferably analkynyl group is a C₂-C₁₂ alkynyl group, which is defined as an alkynylgroup containing from 2 to 12 carbon atoms. More preferably an alkynylgroup is a C₂-C₆ alkynyl group, which is defined as an alkynyl groupcontaining from 2 to 6 carbon atoms. An “alkynylene” group is similarlydefined as a divalent alkynyl group.

An “aryl” group is defined as a monovalent aromatic hydrocarbon.Examples of aryl groups are phenyl, naphthyl, anthracenyl andphenanthrenyl groups. Preferably an aryl group does not include anyheteroatoms in its carbon skeleton. Preferably an aryl group is a C₄-C₁₄aryl group, which is defined as an aryl group containing from 4 to 14carbon atoms. More preferably an aryl group is a C₆-C₁₀ aryl group,which is defined as an aryl group containing from 6 to 10 carbon atoms.An “arylene” group is similarly defined as a divalent aryl group.

Where a combination of groups is referred to as one moiety, for example,arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl oralkynylaryl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule. A typical example of anarylalkyl group is benzyl.

For the purposes of this invention, an optionally substituted alkyl,alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl,alkenylaryl or alkynylaryl group may be substituted with one or mote of—F, —Cl, —Br, —I, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —SH, —NH₂, —CN, —NO₂,—COOH, —R⁴—O—R⁵, —R⁴—S—R⁵, —R⁴—SO—R⁵, —R⁴—SO₂—R⁵, —R⁴—SO₂—OR⁵,—R⁴O—SO₂—R⁵, —R⁴—SO₂—N(R⁵)₂, —R⁴—NR⁵—SO₂—R⁵, —R⁴O—SO₂—OR⁵,—R⁴O—SO₂—N(R⁵)₂, —R⁴—NR⁵—SO₂—OR⁵, —R⁴—NR⁵—SO₂—N(R⁵)₂, —R⁴—N(R⁵)₂,—R⁴—N(R⁵)₃ ⁺, —R⁴—P(R⁵)₂, —R⁴—Si(R⁵)₃, —R⁴—CO—R⁵, —R⁴—CO—OR⁵,—R⁴O—CO—R⁵, —R⁴—CO—N(R⁵)₂, —R⁴—NR⁵—CO—R⁵, —R⁴O—CO—OR⁵, —R⁴O—CO—N(R⁵)₂,—R⁴—NR⁵—CO—OR⁵, —R⁴—NR⁵—CO—N(R⁵)₂, —R⁴—CS—R⁵, —R⁴—CS—OR⁵, —R⁴O—CS—R⁵,—R⁴—CS—N(R⁵)₂, —R⁴—NR⁵—CS—R⁵, —R⁴O—CS—OR⁵, —R⁴O—CS—N(R⁵)₂,—R⁴—NR⁵—CS—OR⁵, —R⁴—NR⁵—CS—N(R⁵)₂ or —R⁵. In this context, —R⁴— isindependently a chemical bond, a C₁-C₁₀ alkylene, C₁-C₁₀ alkenylene orC₁-C₁₀ alkynylene group. —R⁵ is independently hydrogen, unsubstitutedC₁-C₆ alkyl or unsubstituted C₆-C₁₀ aryl. Optional substituent(s) arenot taken into account when calculating the total number of carbon atomsin the parent group substituted with the optional substituent(s).

Any optional substituent may be protected. Suitable protecting groupsfor protecting optional substituents are known in the art, for examplefrom “Protective Groups in Organic Synthesis” by T. W. Greene and P. G.M. Wuts (Wiley-Interscience, 2^(nd) edition, 1991).

For the purposes of this invention, a “salt” is any acid addition salt,preferably a pharmaceutically acceptable acid addition salt, includingbut not limited to a hydrohalogenic acid salt such as hydrofluoric,hydrochloric, hydrobromic and hydroiodic acid salt; an inorganic acidsalt such as nitric, perchloric, sulfuric and phosphoric acid salt; anorganic acid salt such as a sulfonic acid salt (for examplemethanesulfonic, trifluoromethanesulfonic, ethanesulfonic, isethionic,benzenesulfonic, p-toluenesulfonic or camphorsulfonic acid salt),acetic, malic, fumaric, succinic, citric, tartaric, benzoic, gluconic,lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acidsalt; and an aminoacid salt such as ornithinic, glutamic and asparticacid salt. The acid addition salt may be a mono- or di-acid additionsalt. A preferred salt is a di-hydrohalogenic, di-sulphuric,di-phosphoric or di-organic acid salt. A most preferred salt is adi-hydrochloric acid salt.

P is a protected ketone functionality. Suitable protecting groups arecommonly known in the art, for example from Chapter 4 of “ProtectiveGroups in Organic Synthesis” by T. W. Greene and P. G. M. Wuts(Wiley-Interscience, 2^(nd) edition, 1991).

Preferably the protected ketone functionality P is an acyclic ketal orderivative 1q, a cyclic ketal or derivative 1r, 1s or 1t, or a hydrazoneor oxime 1u, as shown in FIG. 4. More preferably P is a cyclic ketal 1r,most preferably P is a monoethyleneketal 1, as shown in FIGS. 2 and 3.

R¹, R² and R³ can be any atom or group. Preferably R¹ and R² are notamine protecting groups. Amine protecting groups are commonly known inthe art, for example from Chapter 7 of “Protective Groups in OrganicSynthesis” by T. W. Greene and P. G. M. Wuts (Wiley-Interscience, 2^(nd)edition, 1991). Most preferably one of R¹ and R² is hydrogen and theother of R¹ and R² is an optionally substituted alkyl, alkenyl, alkynyl,aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl oralkynylaryl group, which may include one or more heteroatoms N, O or Sin its carbon skeleton. Such an optionally substituted alkyl, alkenyl,alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl,alkenylaryl or alkynylaryl group, which may include one or moreheteroatoms N, O or S in its carbon skeleton, does not encompasscarbonyl —CO—R groups, wherein R is any atom or group.

Optionally R¹, R² and R³ are independently hydrogen or an optionallysubstituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl,arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, which mayinclude one or more heteroatoms N, O or S in its carbon skeleton.

Optionally R¹, R² and R³ are independently an alkyl, alkenyl, alkynyl,aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl oralkynylaryl group, which may include one or more heteroatoms N, O or Sin its carbon skeleton, and which may be optionally substituted with oneor more of —F, —Cl, —Br, —I, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —SH, —NH₂,—CN, —NO₂, —COOH, —R⁴—O—R⁵, —R⁴—S—R⁵, —R⁴—SO—R⁵, —R⁴—SO₂—R⁵, —R⁴—N(R⁵)₂,—R⁴—Si(R⁵)₃, —R⁴—CO—R⁵, —R⁴—CO—OR⁵, —R⁴O—CO—R⁵, —R⁴—CO—N(R⁵)₂,—R⁴—NR⁵—CO—R⁵, —R⁴—CS—R⁵ or —R⁵, wherein

-   -   R⁴— is independently a chemical bond, a C₁-C₁₀ alkylene, C₁-C₁₀        alkenylene or C₁-C₁₀ alkynylene group, and    -   R⁵ is independently hydrogen, unsubstituted C₁-C₆ alkyl or        unsubstituted C₆-C₁₀ aryl.

Optionally R¹, R² and R³ are independently an alkyl, alkenyl, alkynyl,aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl oralkynylaryl group, which does not include any heteroatoms in its carbonskeleton, and which may be optionally substituted with one or more of—F, —Cl, —Br, —I, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —SH, —NH₂, —CN, —NO₂,—COOH, —OR⁵, —SR⁵, —SO—R⁵, —SO₂—R⁵, —N(R⁵)₂, —Si(R⁵)₃, —CO—R⁵, —CO—OR⁵,—O—CO—R⁵, —CO—N(R⁵)₂, —NR⁵—CO—R⁵, —CS—R⁵ or —R⁵, wherein

-   -   R⁵ is independently hydrogen, unsubstituted C₁-C₆ alkyl or        unsubstituted C₆-C₁₀ aryl.

Preferably R¹, R² and R³ are independently hydrogen or an unsubstitutedalkyl, aryl or heteroaryl group, which does not include any heteroatomsN, O or S in its carbon skeleton. More preferably, R¹, R² and R³ areindependently hydrogen or an unsubstituted C₁₋₁₀ alkyl group. Morepreferably, R¹, R² and R³ are independently hydrogen or an unsubstitutedC₁₋₆ alkyl group. More preferably, one of R¹ and R² is hydrogen and theother of R¹ and R² is an unsubstituted C₁₋₆ alkyl group, and R³ ishydrogen. Most preferably, one of R¹ and R² is hydrogen and the other ofR¹ and R² is n-propyl, and R³ is hydrogen.

Alternatively, R¹ and R² can, together with the nitrogen to which theyare attached, form a ring. Optionally —NR¹R² together form an optionallysubstituted heterocycloalkyl, heterocycloalkenyl or heteroaryl ring.Optionally —NR¹R² together form

Preferably the reductive amination of step (a) is carried out withNaCNBH₃.

A second aspect of the present invention is a4-amino-cyclohexanone-ethyleneketal 2a or a 4-amino-cyclohexanone 3a

for use in a process of the first aspect of the present invention. R¹and R² are as defined above with reference to the first aspect of thepresent invention. Preferably one of R¹ and R² is hydrogen and the otherof R¹ and R² is n-propyl.

A third aspect of the present invention is a2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole 5a

or a salt thereof, obtained by a process of the first aspect of thepresent invention. R¹, R² and R³ are as defined above with reference tothe first aspect of the present invention. Preferably one of R¹ and R²is hydrogen and the other of R¹ and R² is n-propyl, and R³ is hydrogen.Preferably the compound is a di-hydrochloric acid salt.

The 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles 5a or salts thereofhave at least one chiral centre and can therefore exist in the form ofvarious stereoisomers. The present invention embraces all of thesestereoisomers and mixtures thereof. Mixtures of these stereoisomers canbe resolved by conventional methods, for example, chiral chromatography,fractional recrystallisation, derivatisation to form diastereomers andsubsequent resolution, and resolution using enzymes.

The 2-amino-4,5,6,7-tetrahydro-6-aininobenzothiazole 5a or salt thereofof the present invention preferably comprises at least 95% of the (R)-or the (S)-enantiomer, preferably at least 98% of the (R)- or the(S)-enantiomer, and mote preferably at least 99% of the (R)- or the(S)-enantiomer. Generally, the (S)-enantiomer is the preferredenantiomer.

The 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole 5a or salt thereofmay be used as a medicament, preferably for the treatment of apsychiatric or neurological disorder such as schizophrenia, Alzheimer'sdisease or Parkinson's disease.

A fourth aspect of the present invention is a pharmaceuticalcomposition, comprising 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole5a or salt thereof and a pharmaceutically acceptable carrier or diluent.Preferably the pharmaceutical composition is suitable for the treatmentof a psychiatric or neurological disorder such as schizophrenia,Alzheimer's disease or Parkinson's disease.

A fifth aspect of the present invention is a method of treating apsychiatric or neurological disorder such as schizophrenia, Alzheimer'sdisease or Parkinson's disease, comprising administering atherapeutically effective amount of a2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole 5a or a salt thereof toa subject in need of such treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of the process of the presentinvention.

FIGS. 2 and 3 are schematic illustrations of preferred processes of thepresent invention.

FIG. 4 illustrates preferred protected ketone functionalities P.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have found that processes for the preparation of2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles 5a are greatly improvedby the process outlined in FIG. 1, wherein R¹ and R² can be any atom orgroup or, together with the nitrogen to which they are attached, form aring, and wherein R³ can be any atom or group. R¹, R² and R³ arepreferably hydrogen or an unsubstituted alkyl, aryl or heteroaryl group.

The process outlined in FIG. 1 is short, utilises a readily availablestarting material, a protected cyclohexandione 1p, and does not requireany hazardous chemical reagents. Each step of the process is highyielding and affords products of very high purity.

Therefore a first aspect of the current invention is a process for thepreparation of 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles 5a bythe process specified in FIG. 1.

It has been disclosed in prior art documents WO 02/22590 and WO 02/22591that, in practice, compounds of formula 5a, comprising a primary aminoor a secondary alkylamino group, cannot be prepared directly from thecorresponding ketones 3a. The process shown in FIG. 1, however,illustrates that the process of the current invention does indeed allowa compound 5a to be prepared from ketones 3a directly without therequirement of preparing and isolating an α-haloketone of formula 4,where X is a halide such as chloride or bromide, or the requirement of aprotecting group on the nitrogen atom of the amine substituent —NR¹R² ofthe ketone 3a.

Therefore, in a preferred embodiment of the present invention, theα-haloketone of formula 4 is not isolated. Moreover, in a preferredembodiment of the present invention, the nitrogen atom of the aminesubstituent —NR¹R² of the ketone 3a is not protected.

In a preferred embodiment of the first aspect of the invention,cyclohexandione is protected as a cyclohexandione monoethyleneketal 1,as shown in FIGS. 2 and 3.

A further preferred embodiment of the first aspect of the invention is aprocess for the preparation of2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole 5, as outlinedin FIG. 3.

The process outlined in FIG. 3 can readily be adapted to affordpramipexole I or its salts, for example by resolution of compound 5.Methods for resolving enantioners are well known in the art and include,for example, chiral chromatography, fractional recrystallisation,derivatisation to form diastereomers and subsequent resolution, andresolution using enzymes.

A further aspect of the invention is therefore pramipexole I and itssalts, when prepared by a process according to the current invention.

Further aspects of the invention include novel compounds of the formula2a or 3a, wherein R¹ and R² are as defined above, which are usefulintermediates in the synthesis of2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles 5a.

Preferred embodiments of these aspects are compounds 2 and 3, as shownin FIG. 3.

The process outlined in FIG. 3 is an example of a procedure comprisingthe process of the current invention and detailed procedures for thisprocess are found in the experimental section. Compounds of the currentinvention are also exemplified in FIG. 3 and in the experimentalsection.

The process of the present invention is short, utilises readilyavailable starting materials and does not involve the use of hazardousor difficult to handle reagents such as bromine, hydrazine or potassiumchromate. Each step of the process of the present invention is highyielding and affords products of very high purity. Thus the process iseasy to scale up for industrial scale manufacturing. Optionally2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazoles 5a and salts thereofmay be manufactured in batches of 5 kg or more, or even 10 kg or more.

Experimental procedure

4-n-Propylamino-cyclohexanone-ethyleneketal 2

A mixture of n-propyl amine (162 ml, 1.474 mol) in methanol (500 ml) waschilled to 0-5° C. To this solution was added methanolic hydrochloricacid (155 ml, 44.47%) dropwise over a period of 30 minutes to achieve apH of 6-7. Cyclohexandione monoethyleneketal 1 (100 g, 0.641 mol) wascharged at 5° C. and the reaction was stirred for 15 minutes. Sodiumcyanoborohydride (60 g, 0.952 mol) was added in 15 minutes at 5° C. ThepH increased to about 8 and methanolic hydrochloric acid (15 ml, 44.47%)was added to bring the pH to 6-7. The reaction was allowed to come to24-26° C. Stirring was continued for 2 hours. Methanol was distilled off(450 ml). Sodium carbonate (95 g, 0.896 mol) was dissolved in water (850ml) and charged to the reaction mass at ambient temperature in one shot.The reaction mass was extracted with dichloromethane (2500 ml). Thedichloromethane layers were combined and dried over sodium sulfate (8.5g). The dichloromethane layer was concentrated to dryness at 40° C. and15 mbar pressure. The product 2 was light yellow viscous oil. The weightof the product 2 obtained was 135 g (105.8%); GC purity 97.74%.

¹H NMR (δ ppm): 0.9-1.0 (t, 3H, CH₃ of nPr); 1.5-1.7 (m, 7H, CH ₂CH₃ ofnPr and 5H of cyclohexyl ring); 1.75-1.85 (m, 2H, 2H of cyclohexylring); 1.95-2.05 (m, 1H, 1H of cyclohexyl ring); 2.75 (t, 2H, CH ₂CH₂CH₃of nPr); 3.75-3.85 (m, 1H, NHCH); 3.9 (s, 2H, CH₂ of ethylene ketal) and4.0 (s, 2H, CH₂ of ethylene ketal).

¹³C NMR (δ ppm): 11.7 (CH₃ of nPr); 21.8 (CH ₂CH₃ of nPr); 28.5 (C-3 andC-5); 33.1 (C-2 and C-6); 48.3 (CH ₂CH₂CH₃ of nPr); 55.8 (C-4); 64.5 (Cof ethylene ketal); 64.6 (C of ethylene ketal); 108.1 (C-1).

4-n-Propylamino-cyclohexanone 3

4-N-propylamino-cyclohexanone-ethyleneketal 2 (134 g, 0.673 mol) wastaken in tetrahydrofuran (268 ml) and cooled to 4-6° C. Concentratedhydrochloric acid (178 ml, 2.01 mol) was diluted with water (2144 ml)and the mixture was cooled to 4° C. This diluted hydrochloric acid wasadded to the reaction mixture at 4-6° C. in 15 minutes. The reaction wasallowed to come to 24-26° C. and stirring was continued for 24 hours.The reaction mass (2750 ml) was concentrated to 1800 ml at 50° C. and 35mbar pressure. Sodium carbonate (148 g, 1.4 mol) was added to achieve pH10. The reaction mixture was extracted with dichloromethane (3670 ml).The dichloromethane layers were combined and dried over sodium sulfate(20 g). The dichloromethane layer was concentrated to dryness at 40° C.and 15 mbar pressure. The product 3 was yellow viscous oil. The weightof the product 3 obtained was 52.5 g (52.84%); GC purity 86.07%.

¹H NMR (δ ppm): 0.9-1.0 (t, 3H, CH₃ of nPr); (m, 2H, CH ₂CH₃ of nPr);1.6-1.75 (m, 2H, 2H of cyclohexyl ring); 2.05-2.15 (m, 2H, 2H ofcyclohexyl ring); 2.2-2.3 (m, 2H, 2H of cyclohexyl ring); 2.4-2.55 (m,2H, 2H of cyclohexyl ring); 2.55-2.65 (t, 2H, CH ₂CH₂CH₃ of nPr);2.9-3.0 (m, 1H, NHCH).

¹³C NMR (δ ppm): 12.3 (CH₃ of nPr); 24.0 (CH₂CH₃ of nPr); 32.6 (C-3 andC-5); 39.1 (C-2 and C-6); 50.0 (CH₂CH₂CH₃ of nPr); 54.4 (C-4); 211.9(C-1).

2-Amino-6-n-propylamino-5,6,7,8-tetrahydrobenzthiazole 5

4-n-Propylamino-cyclohexanone 3 (5 g, 32.26 mmol) was charged inabsolute ethanol (50 ml) at 24-26° C. Iodine (8.5 g, 33.5 mmol) wasadded to it under stirring followed by thiourea (5 g, 65.7 mmol) at24-26° C. The reaction mass was refluxed for 32 hours. Heating wasstopped and the reaction mass was allowed to cool to 24-26° C. It wasmaintained at that temperature for 20 hours.2-Amino-6-n-propylamino-5,6,7,8-tetrahydrobenzthiazole dihydroiodidesalt crystallized out of the solution. Ethanol (30 ml) was distilled outon the rotavapor at 50° C. and 100 mbar. Acetone (50 ml) was added andthe solid was filtered. The solid was dried at 40° C. and 15 mbar. Theweight of the product obtained was 8.5 g (56%); HPLC purity 94.97%.

¹H NMR (δ ppm): 0.9-1.0 (t, 3H, CH₃ of nPr) 1.6-1.8 (m, 2H, CH ₂CH₃ ofnPr); 2.0 (m, 1H, H-7a); 2.35 (m, 1H, H-7b); 2.7 (m, 3H, H-5a, H-8a,H-8b); 3.1 (m, 3H, H-5b and CH ₂CH₂CH₃ of nPr); 3.7 (m, 1H, NHCH).

¹³C NMR (δ ppm): 12.0 (CH₃ of nPr); 21.0 (CH₂CH₃ of nPr); 22.2 (C-7);25.5 and 26.8 (C-5 and C-8); 48.7 (CH₂CH₂CH₃ of nPr); 54.7 (C-6); 113.0(C-4); 134 (C-9); 171.2 (C-2).

Mass Spec: M⁺ 211 (expected 211).

The 2-amino-6-n-propylamino-5,6,7,8-tetrahydrobenzthiazole dihydroiodidesalt formed above (50 g, 107.1 mmol) was dissolved in water (200 ml).The solution was cooled to 4° C. and solid sodium hydroxide (50 g, 1.25mol) was added in 15 minutes. The reaction was stirred for 1 hour at24-26° C. and the solid that precipitated out was filtered and dried at40° C. and 15 mbar. The weight of the product 5 obtained was 17.07 g(75.5%); HPLC purity 99.88%.

¹H NMR (δ ppm): 0.9-1.0 (t, 3H, CH₃ of nPr); 1.5-1.6 (m, 2H, CH ₂CH₃ ofnPr); 2.1 (m, 1H, H-7a); 2.3 (m, 1H, H-7b); 2.5-2.6 (m, 5H, H-5a, H-5b,H-8a, H-8b and CHCH₂CH₃ of nPr); 2.9 (m, 2H, H-6 and CHCH₂CH₃ of nPr).

¹³C NMR (δ ppm): 12.0 (CH₃ of nPr); 24.6 (CH₂CH₃ of nPr); 26.6 (C-7);30.7 and 30.9 (C-5 and C-8); 50.7 (CH₂CH₂CH₃ of nPr); 56.2 (C-6); 116.0(C-4); 145 (C-9); 170.4 (C-2).

Mass Spec: M⁺ 211 (expected 211).

It will be understood that the present invention has been describedabove by way of example only. The examples are not intended to limit thescope of the invention. Various modifications and embodiments can bemade without departing from the scope of the invention, which is definedby the following claims.

1. A process for the preparation of a2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole 5a

or a salt thereof, comprising the steps of: (a) reductively aminating aprotected cyclohexandione 1p with an amine R¹R²NH to yield a protected4-amino-cyclohexanone 2p:

wherein P is a protected ketone functionality, and R¹ and R² are anyatom or group or, together with the nitrogen to which they are attached,form a ring; (b) deprotecting the protected 4-amino-cyclohexanone 2p toyield an unprotected 4-amino-cyclohexanone 3a

(c) treating the unprotected 4-amino-cyclohexanone 3a with iodine and asubstituted thiourea H₂N(C═S)NHR³, wherein R³ is any atom or group, toyield the 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole 5a or a saltthereof.
 2. A process as claimed in claim 1, wherein P is a cyclic ketal1r.
 3. A process as claimed in claim 2, wherein P is amonoethyleneketal
 1. 4. A process as claimed in claim 1, wherein R¹,R²and R³ are independently hydrogen or an optionally substituted alkyl,alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl,alkenylaryl or alkynylaryl group, which may include one or moreheteroatoms N, O or S in its carbon skeleton.
 5. A process as claimed inclaim 1, wherein R¹, R² and R³ are independently hydrogen or anunsubstituted alkyl, aryl or heteroaryl group, which does not includeany heteroatoms N, O or S in its carbon skeleton.
 6. A process asclaimed in claim 1, wherein one of R¹ and R² is hydrogen and the otherof R¹ and R² is an optionally substituted alkyl, alkenyl, alkynyl, aryl,arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl oralkynylaryl group, which may include one or more heteroatoms N, O or Sin its carbon skeleton
 7. A process as claimed in claim 6, wherein oneof R¹ and R² is hydrogen and the other of R¹ and R² is n-propyl.
 8. Aprocess as claimed in claim 1, wherein R³ is hydrogen.
 9. A process asclaimed in claim 1, wherein the reductive amination of step (a) iscarried out with NaCNBH₃.
 10. (canceled)
 11. (canceled)
 12. A process asclaimed in claim 25, wherein one of R¹ and R² is hydrogen and the otherof R¹ and R² is n-propyl. 13-24. (canceled)
 25. A process for thepreparation of a 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole 5a

or a salt thereof, comprising the steps of: (a) reductively aminating aprotected cyclohexandione 1 with an amine R¹R²NH to yield a protected4-amino-cyclohexanone 2a:

wherein R¹ and R² are any atom or group or, together with the nitrogento which they are attached, form a ring; (b) deprotecting the protected4-amino-cyclohexanone 2a to yield an unprotected 4-amino-cyclohexanone3a

(c) treating the unprotected 4-amino-cyclohexanone 3a with iodine and asubstituted thiourea H₂N(C═S)NHR³, wherein R³ is any atom or group, toyield the 2-amino-4,5,6,7-tetrahydro-6-aminobenzothiazole 5a or a saltthereof.